ABSTRACT
An adenosine A2A receptor antagonist may be useful for the treatment of Parkinson's disease. Synthesis and structure-activity studies starting from 4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063, 4) led to a novel series of human (h) A2A receptor antagonists with improved aqueous solubility. Compound 22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound 22 also displayed good in vitro pharmacokinetic properties and is considered a good starting point for further lead optimisation toward hA2A receptor antagonists with improved druggability properties.
Subject(s)
Adenosine A2 Receptor Antagonists/chemical synthesis , Receptor, Adenosine A2A/chemistry , Thiazoles/chemical synthesis , para-Aminobenzoates/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/metabolism , Binding Sites , Humans , Ligands , Molecular Docking Simulation , Protein Binding , Receptor, Adenosine A2A/metabolism , Solubility , Structure-Activity Relationship , Thiazoles/chemistry , Water/chemistry , para-Aminobenzoates/chemistryABSTRACT
Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7â Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.
Subject(s)
Adaptor Proteins, Vesicular Transport/antagonists & inhibitors , Adaptor Proteins, Vesicular Transport/chemistry , Coumarins/chemistry , Leucine/analogs & derivatives , Small Molecule Libraries/chemistry , Adaptor Proteins, Vesicular Transport/genetics , Binding Sites , Crystallization , Crystallography, X-Ray , HEK293 Cells , Humans , Leucine/chemistry , Ligands , Neurotensin/chemistry , Phenylalanine/chemistry , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.
Subject(s)
Adaptor Proteins, Vesicular Transport/antagonists & inhibitors , Hydrocarbons, Fluorinated/pharmacology , Pyridines/pharmacology , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Models, Molecular , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Herein we describe the discovery of a series of novel adenosine A(2A) receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson's Disease.
